Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease - PubMed (original) (raw)

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Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease

Lavinia C Dumitrache et al. Mech Ageing Dev. 2017 Jan.

Abstract

A variety of human neurologic diseases are caused by inherited defects in DNA repair. In many cases, these syndromes almost exclusively impact the nervous system, underscoring the critical requirement for genome stability in this tissue. A striking example of this is defective enzymatic activity of polynucleotide kinase-phosphatase (PNKP), leading to microcephaly or neurodegeneration. Notably, the broad neural impact of mutations in PNKP can result in markedly different disease entities, even when the inherited mutation is the same. For example microcephaly with seizures (MCSZ) results from various hypomorphic PNKP mutations, as does ataxia with oculomotor apraxia 4 (AOA4). Thus, other contributing factors influence the neural phenotype when PNKP is disabled. Here we consider the role for PNKP in maintaining brain function and how perturbation in its activity can account for the varied pathology of neurodegeneration or microcephaly present in MCSZ and AOA4 respectively.

Keywords: Base excision repair; DNA damage signaling; DNA repair; Microcephaly; Neurodegeneration; Neurologic disease; Polynucleotide kinase phosphatase; Single strand break repair.

Copyright © 2016. Published by Elsevier B.V.

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Figures

Figure 1

Figure 1. Disease-causing mutations in PNKP

The upper diagram shows the PNKP protein with the forkhead-associated domain (FHA), and the phosphatase and kinase domains indicated. The numbering indicates specific amino acid residues, and also the germline mutation changes found in PNKP in human syndromes. MCSZ mutations are listed in black, AOA4 mutations are purple and blue are mutations found in a compound heterozygote that showed an MCSZ phenotype. The P20S mutation in green is from an individual who manifest only seizures, but not neurodegeneration or microcephaly. The T424GfsX48 common mutation is present in homozygous individuals with MCSZ and also in siblings with both MCSZ, and in a compound heterozygous form in AOA4. The lower illustration indicates the effect of the T424GfsX48 change in the PNKP protein, showing premature termination in the kinase domain.

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